Huisman, M., van den Bosch, M.A., Wijlemans, J.W., van Vulpen, M., van der Linden, Y.M., & Verkooijen, H.M. (2012). Effectiveness of reirradiation for painful bone metastases: A systematic review and meta-analysis. International Journal of Radiation Oncology, Biology, Physics, 84, 8–14.

STUDY PURPOSE: To assess pain response after reirradiation in patients with painful bone metastases not sufficiently responding to initial radiation therapy or exhibiting recurrent pain after initial response

TYPE OF STUDY: Combined systematic review and meta-analysis

DATABASES USED: MEDLINE, EMBASE, and Cochrane Collaboration library

KEYWORDS: Radiotherapy, reirradiation, retreatment, bone metastases, palliative treatment

INCLUSION CRITERIA: All types of studies were allowed. Participants received reirradiation at the initial site of radiation for radiation-refractory metastatic bone pain. Both the initial treatment and retreatment consisted of external beam radiation therapy (EBRT). Reported outcomes were reported at least in response to initial reirradiation, and original research data were reported. If eligibility for inclusion could not be decided based on abstract screening, or if the abstract was not available, the full-text article was reviewed. To qualify for the meta-analysis, the study had to meet additional criteria: outcomes were available on an individual patient level, and the size of the study population was 10 patients or more.

EXCLUSION CRITERIA: Languages other than English, German, French, and Dutch

TOTAL REFERENCES RETRIEVED: 707

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Authors were contacted for missing data. Publication quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) method. Data extraction and quality assessment was performed independently by two observers.

• FINAL NUMBER STUDIES INCLUDED = 10 (qualitative synthesis), 7 (meta-analysis)
• TOTAL PATIENTS INCLUDED IN REVIEW = 440
• SAMPLE RANGE ACROSS STUDIES: 11%–24% of patients observed received reirradiation, numbering from 4–173 cases
• KEY SAMPLE CHARACTERISTICS: Sample characteristics were available in two studies. One study (Van Der Linden et al.) reported that 61% of participants were male, 39% were female, the mean age was 65, and the mean Karnofsky Performance Status was 70. In a second study (Hayalshi et al.), it was reported that 57% of participants were male, 43% were female, the median age was 60, and the mean Eastern Cooperative Oncology Group (ECOG) performance status score was 2.5. Primary tumor types were breast (33%), prostate (21%), lung (23%), and other tumor types (23%). Reirradiated sites were localized to the spine (36%), pelvis (38%), proximal long bones (12%), and other locations (14%). Most patients were treated with single-fraction radiotherapy.

PHASE OF CARE: Transitional care after initial treatment

APPLICATIONS: Late-effects, survivorship, and palliative care

In this meta-analysis, 264 out of 440 patients achieved either complete or partial response with an overall response rate of 58%. Sensitivity analysis was not feasible. The complete response rate for reirradiation ranged from 16%–28%, and partial response rates were 28%–45%. Pooling was not appropriate due to the low number of studies. The time to response after reirradiation ranged from three to five weeks.

Approximately 60% of patients derived some benefit from the reirradiation of radiation-refractory bone pain. The time to response was three to five weeks. For those receiving reirradiation in a circumstance in which the end of life is near, this method may not be effective. Remission of pain, however, was reported to last anywhere from 15–22 weeks.

Not all studies reported drop-out rates and so an intention to treat analysis was not feasible. If reported, however, drop-out rates ranged from 14%–35%. These rates were attributed to death and symptomatic relief but were not clear, so bias could not be excluded. Further, no randomized, controlled trial has been published on reirradiation treatment for radiation-refractory metastatic bone pain. There is limited evidence on reirradiation effectiveness, study quality is mediocre, and populations are small. Also, the difference in study design, clinical differences between study populations, lack of clinical guidelines for reirradiation, and changes in insight over time contributed to the heterogeneity observed in the included studies. All of these factors again support the need for ongoing investigation of reirradiation for bone metastases and further investigation of palliative care measures to provide optimal relief for patients with painful bone metastases.